Age is the major risk factor for many morbidities including cancer, cardiovascular and neurodegenerative diseases. Biogerontology research is well positioned to help prevent or at least delay these diseases by identifying safe strategies to retard aging so that the degree and type of cellular damage does not reach the threshold required for disease incidence or progression. Here we propose to bring together two biogerontology laboratories from the University of Southern California School of Gerontology and a laboratory from Harvard University to study the molecular mechanisms linking fasting and protein restriction to reduced growth factor signaling, the stress resistance signaling network, the mitochondrial peptide humanin, and in turn, cellular protection, regeneration, and healthspan. These studies will contribute to the identification of drugs and dietary interventions to treat as well as prevent multiple diseases by acting on the aging process and on multi-system regeneration and rejuvenation. An important advantage of the dietary interventions being tested is that they are periodic and therefore have the potential to match and possibly surpass the beneficial effects of chronic calorie restriction while minimizing the burden of chronic and extreme diets, but also minimizing adverse effects. This P01 renewal application consists of 3 major projects, an Animal and Biostatistics Core, and an Administrative Core. Our common goals are to: 1) study previously established and identify novel periodic dietary interventions tha promote healthspan without causing adverse effects at old ages; 2) study the mechanisms of fasting and protein restriction-dependent cellular protection, regeneration and rejuvenation with focus on the hematopoietic and nervous systems; 3) understand the link between dietary interventions, growth pathways and humanin to test the hypothesis that this mitochondrial peptide functions as a healthspan mediator and determine whether it can serve as a fasting/protein restriction mimetic; 4) test the hypothesis that endogenous H2S is a key mediator of the protective effects of dietary interventions including fasting and protein restriction on resistance to ischemic and genotoxic injury to organs and cells, and study the regulation of cysteine gamma lyase-mediated endogenous H2S production by dietary restriction, growth factors and humanin. The unique background of each PI and the close collaborations between them has generated and will continue to generate new hypotheses, a variety of novel cellular and mouse models, assays, and technical and conceptual developments. These advances, will undoubtedly accelerate the research progress, and support the development of clinical trials to improve human health in ways that could not be achieved by each laboratory performing this research independently.